Halogen bonds are noncovalent interactions in which covalently bound halogens act as electrophilic species. The utility of halogen bonding for controlling self-assembly in the solid state is evident from a broad spectrum of applications in crystal engineering and materials science. Until recently, it has been less clear whether, and to what extent, halogen bonding could be employed to influence conformation, binding or reactivity in the solution phase. This tutorial review summarizes and interprets solution-phase thermodynamic data for halogen bonding interactions obtained over the past six decades and highlights emerging applications in molecular recognition, medicinal chemistry and catalysis.

The cardiac glycoside natural product digitoxin was selectively glycosylated at one of its five hydroxyl groups using a borinic acid derived catalyst. This method provided access to the glycosylation pattern characteristic of a subclass of natural products from Digitalis purpurea. Variation of the glycosyl donor was tolerated, enabling the synthesis of novel cardiac glycoside analogs from readily available materials.

A borinic acid derived catalyst enables regioselective and β-selective reactions of 2-deoxy- and 2,6-dideoxyglycosyl chloride donors with pyranoside-derived acceptors having unprotected cis-1,2- and 1,3-diol groups. The use of catalysis to promote a β-selective pathway by enhancement of acceptor nucleophilicity constitutes a distinct approach from previous work, which has been aimed at modulating donor reactivity by variation of protective and/or leaving groups.

The combretastatins have been investigated for their antimitotic and antivascular properties, and it is widely postulated that a 3,4,5-trimethoxyaryl A-ring is essential to maintain potent activity. We have synthesized new tetrazole analogues (32-34), demonstrating that 3,5-dihalogenation can consistently increase potency by up to 5-fold when compared to the equivalent trimethoxy compound on human umbilical vein endothelial cells (HUVECs) and a range of cancer cells. Moreover, this increased potency offsets that lost by installing the tetrazole bridge into combretastatin A-4 (1), giving crystalline, soluble compounds that have low nanomolar activity, arrest cells in G2/M phase, and retain microtubule inhibitory activity. Molecular modeling has shown that optimized packing within the binding site resulting in increased Coulombic interaction may be responsible for this improved activity.

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